Cure Alzheimer's Fund - Drug Discoveryhttp://curealz.org/topics/drug-discovery
enAlzstream™ Webinar: From Genes to Therapieshttp://curealz.org/2015/02/alzstream%E2%84%A2-webinar-genes-therapies
<div class="field field-name-field-video field-type-file field-label-hidden"><div class="field-items"><div class="field-item even"><div class="media-vimeo-video media-vimeo-1">
<iframe class="media-vimeo-player" width="770" height="433" title="119473473" src="//player.vimeo.com/video/119473473?color=01AAEA" frameborder="0" allowfullscreen>Video of 119473473</iframe>
</div>
</div></div></div><div class="field field-name-field-topics field-type-taxonomy-term-reference field-label-inline clearfix"><div class="field-label">Keywords:&nbsp;</div><div class="field-items"><div class="field-item even"><a href="/topics/drug-discovery">Drug Discovery</a></div></div></div>Fri, 06 Feb 2015 16:31:26 +0000madelson4666 at http://curealz.orgFeatured Researcher: Charles G. Glabe, Ph.D.http://curealz.org/2014/11/featured-researcher-charles-g-glabe-phd
<div class="field field-name-field-image field-type-image field-label-hidden pull-right"><div class="field-items"><div class="field-item even"><img src="http://curealz.org/sites/default/files/styles/large/public/stories/Glabe%2CCharlie_RGB.jpg?itok=A-MvKnvz" width="377" height="480" alt="" /></div></div></div><div class="field field-name-body field-type-text-with-summary field-label-hidden"><div class="field-items"><div class="field-item even"> <p><em>From the age of 2, when he disassembled his brother’s mechanical duck and his father praised him for his curiosity, Charlie Glabe was always interested in the way things work. In college he supported himself as a car mechanic, but found his true passion in scientific research. Today Charlie is a highly respected neuroscientist and a member of the Cure Alzheimer’s Fund Research Consortium.</em></p>
<p> </p>
<p><strong>Early days</strong></p>
<p>Charlie Glabe was born in Columbus, Ohio, the second of three boys. When he was still a baby, his father moved the family to California for a position as a mathematics professor at Sacramento State College. His mother had been a high school English teacher, but after the move decided to stay home with her children.</p>
<p>In high school, Glabe’s science classes were “kind of bland,” he said. “Girls were much more interesting.” But when he attended Sacramento State College as a biology major, he discovered the joys of science. Glabe worked his way through college as a Volkswagen mechanic, which he now compares to research. “You’re under pressure to get the job done. You need to explore every possibility to figure out what’s wrong, eliminating the easiest things first. And it teaches you humility.” After getting his degree, Glabe wanted to work for the California Fish and Game Commission, but when he didn’t get the job (because he wasn’t a Vietnam war vet), he went to plan B: graduate school. “It turns out that I’m a better scientist than I ever would have been a bureaucrat.”</p>
<p>In 1973, Glabe attended the University of California’s (UC) graduate program to study cell biology, developmental biology and biochemistry. That’s when he met his wife, a family planning and domestic violence counselor, and built a life that came to include their three grown children. Glabe moved to the East Coast for a few years to become a postdoctoral fellow at The Johns Hopkins University School of Medicine, where he honed his skills as a biochemist. In 1980, he became a postdoctoral fellow at UC, San Francisco, then a staff scientist at the Worcester (Massachusetts) Foundation for Experimental Biology. In 1985, he returned to California as an assistant professor at UC, Irvine.</p>
<p> </p>
<p><strong>Alzheimer’s</strong></p>
<p>Glabe’s big break came later that year when he was working on the biology of marine animals. A friend of his who was working with the noted neuroscientist Carl Cotman asked Glabe for help with a very different experiment. They needed a particular peptide, or protein fragment, for their research. “He had the sequence written down on a piece of paper and said he’d give me $30,000 and a technician salary for a year to make it.” Glabe realized then this was no ordinary peptide; as it happened, he became one of the first people in the world to artificially manufacture Abeta, the famous toxic hallmark of Alzheimer’s disease. “My friend told me that Abeta caused Alzheimer’s and that I should be careful. So I started reading about it, and a light bulb went off in my head. This was something I wanted to work on,” said Glabe. “That’s when I became interested in intercellular amyloid. In 1992, we were looking for a receptor for a beta peptide. I thought it would be easy, but we soon discovered that the long form of Abeta was immortal, while the short form was easily degraded. In the process, we realized that cells could live for a long time despite Abeta accumulation—like a slow-growing tumor that ultimately takes over.”</p>
<p>In 2007, Glabe received a Cure Alzheimer’s Fund (CAF) grant to produce as many antibodies against Abeta as possible. (One promising strategy to combat Alzheimer’s is to use such antibodies as a vaccine to rid the body of the toxin as it accumulates.) Glabe originally had thought Abeta could fold up in only one way, but he soon discovered it could fold up in many different ways and that different antibodies can recognize and bind to these different <em>foldomers</em>. “This went against all our assumptions,” explained Glabe. “It turned out there were 23 antibodies—many more than we had expected—and we needed to test them right away before they died. I called [Cure Alzheimer’s Fund CEO] Tim Armour to ask for more money and he came through. It turned out that one of these antibodies reacted with a unique type of intranuclear amyloid that had never been seen before.” That finding charted Glabe’s path.</p>
<p>In 2010, the pharmaceutical giant Eli Lilly ran a clinical trial for Semagacestat, a gamma secretase <em>inhibitor, </em>as the first potentially disease-modifying drug for Alzheimer’s. Rather than helping the test group, the drug actually made them cognitively worse. Many companies working on similar drugs subsequently ended their Alzheimer’s programs, while many dedicated researchers—including Glabe—did a lot of soul searching. “When a drug has the opposite effect that you want it to have,” he said, “the simplest explanation is that we were thinking about the disease mechanism backwards.” He went back to the drawing board and developed a mirror image of the working amyloid hypothesis. “The Eli Lilly drug prevents the secretion of soluble Abeta, and we think that this causes the neuronal retention of insoluble Abeta,” Glabe explained. “These are mirror image mechanisms. When you decrease secreted soluble Abeta, you increase intraneuronal insoluble Abeta. That is the new amyloid hypothesis.”</p>
<p>His work ultimately supported the idea that gamma secretase <em>modulators </em>would be effective therapeutics vs. gamma secretase <em>inhibitors, </em>which only made patients worse. “You have to be fearless to say that 98 percent of people have been thinking about the disease backwards. But that’s the kind of research Cure Alzheimer’s Fund encourages,” said Glabe. </p>
<p>These days Charlie spends most of his time in his lab, although he teaches two classes a year. “I love science. I’m addicted to doing experiments and getting results. Everyone who’s part of the Cure Alzheimer’s Fund Research Consortium is doing cutting-edge work. And we have a diverse range of talent that proves that the whole is really greater than the sum of its parts.”</p>
</div></div></div><div class="field field-name-field-topics field-type-taxonomy-term-reference field-label-above"><div class="field-label">Keywords:&nbsp;</div><div class="field-items"><div class="field-item even"><a href="/topics/drug-discovery">Drug Discovery</a></div></div></div>Fri, 07 Nov 2014 21:48:01 +0000madelson4256 at http://curealz.orgThe State of Alzheimer's Research, 2014http://curealz.org/2014/10/state-alzheimers-research-2014
<div class="field field-name-body field-type-text-with-summary field-label-hidden"><div class="field-items"><div class="field-item even"> <p><a href="http://curealz.org/people/rudy-tanzi" target="_blank">Dr. Rudy Tanzi</a>, chairman of the Cure Alzheimer's Fund Research Consortium, presents on the current state of Alzheimer's research. Dr. Tanzi focuses on the importance of the recent "<a href="http://curealz.org/2014/10/%E2%80%9Cgame-changer%E2%80%9D-new-york-times-trumpets-%E2%80%9Cgiant-step-forward%E2%80%9D-tanzi-lab" target="_blank">Alzheimer's in a Dish</a>" study.</p>
<p>This footage was recorded at our event <a href="http://curealz.org//events/2014/05/2014-fall-symposium-10-years-leading-research" target="_blank">Celebrating 10 Years of Leading Research: 10th Anniversary and Symposium.</a></p>
</div></div></div><div class="field field-name-field-video field-type-file field-label-hidden"><div class="field-items"><div class="field-item even"><div class="media-vimeo-video media-vimeo-2">
<iframe class="media-vimeo-player" width="770" height="433" title="110252647" src="//player.vimeo.com/video/110252647?color=01AAEA" frameborder="0" allowfullscreen>Video of 110252647</iframe>
</div>
</div></div></div><div class="field field-name-field-topics field-type-taxonomy-term-reference field-label-inline clearfix"><div class="field-label">Keywords:&nbsp;</div><div class="field-items"><div class="field-item even"><a href="/topics/alzheimers-causes-risk-factors">Alzheimer&#039;s Causes &amp; Risk Factors</a></div><div class="field-item odd"><a href="/topics/drug-discovery">Drug Discovery</a></div><div class="field-item even"><a href="/topics/symposium">Symposium</a></div><div class="field-item odd"><a href="/topics/genes-therapies%E2%84%A2">Genes to Therapies™</a></div></div></div>Tue, 21 Oct 2014 20:42:04 +0000madelson4156 at http://curealz.orgAn “Inside-Out View” of Alzheimer’s: Study Offers New Take on Amyloid Hypothesishttp://curealz.org/2014/08/%E2%80%9Cinside-out-view%E2%80%9D-alzheimer%E2%80%99s-study-offers-new-take-amyloid-hypothesis
<div class="field field-name-field-byline field-type-node-reference field-label-hidden"><div class="field-items"><div class="field-item even"><a href="/people/david-shenk">David Shenk</a></div></div></div><div class="field field-name-field-image field-type-image field-label-hidden pull-right"><div class="field-items"><div class="field-item even"><img src="http://curealz.org/sites/default/files/styles/large/public/stories/glabe%20story%20amyloid%20image.jpg?itok=XdfBAvQf" width="480" height="356" alt="" /></div></div></div><div class="field field-name-body field-type-text-with-summary field-label-hidden"><div class="field-items"><div class="field-item even"> <p class="p1">A new "alternative amyloid hypothesis” from the lab of <a href="http://curealz.org/people/charles-glabe">Dr. Charles Glabe</a>, at the University of California at Irvine, helps explain precisely how neurons (nerve cells) die in Alzheimer’s disease and how known genetic mutations initiate a chain reaction in this long process. The important new hypothesis was driven by research supported by Cure Alzheimer’s Fund, and has just been being published in the Journal <em>Neurobiology of Disease</em>. Dr. Glabe is a longtime member of Cure Alzheimer’s Fund<span style="line-height: 1.42857143;">’</span><span style="line-height: 1.42857143;">s Research Consortium.</span></p>
<p class="p1">The new approach is an “inside-out view” of Alzheimer’s, according to Glabe. The traditional view is that the protein fragment beta-amyloid aggregates into plaques outside neurons and subsequently causes stress and death to those neurons. Glabe's new hypothesis proposes the reverse order: beta-amyloid forms first within the neuron, causing cell death, which subsequently spurs the formation of neuritic plaques. "It also has therapeutic implications,” he adds. "It suggests that gamma secretase modulators of the type that are being developed by Consortium member <a href="http://curealz.org/people/steven-wagner">Dr. Steven Wagner</a> will be successful because they will increase the secretion of soluble Abeta species and prevent the intraneuronal accumulation that leads to neuron death.” (Find out more about Dr. Wagner's work <a href="http://curealz.org/2014/03/inside-alzheimers-lab-steven-wagner-phd">here</a>.)</p>
<p class="p1">“This represents an important challenge to our thinking,” says <a href="http://curealz.org/people/rudy-tanzi">Dr. Rudy Tanzi</a>, Chair of the Cure Alzheimer’s Fund Research Consortium. “The amyloid hypothesis has been strongly confirmed in recent years by our genetic and other research. But it’s important that we keep refining it, in order to continually improve intervention strategies.”</p>
<p class="p2">Read an abstract of the journal article <a href="http://www.ncbi.nlm.nih.gov/pubmed/25092575">here</a>.</p>
</div></div></div><div class="field field-name-field-topics field-type-taxonomy-term-reference field-label-above"><div class="field-label">Keywords:&nbsp;</div><div class="field-items"><div class="field-item even"><a href="/topics/research-updates">Research Updates</a></div><div class="field-item odd"><a href="/topics/drug-discovery">Drug Discovery</a></div></div></div>Thu, 14 Aug 2014 17:50:00 +0000madelson4001 at http://curealz.orgAre Brain Cell Regeneration Drugs Ready for Prime Time?http://curealz.org/2014/08/are-brain-cell-regeneration-drugs-ready-prime-time
<div class="field field-name-field-byline field-type-node-reference field-label-hidden"><div class="field-items"><div class="field-item even"><a href="/people/david-shenk">David Shenk</a></div></div></div><div class="field field-name-field-image field-type-image field-label-hidden pull-right"><div class="field-items"><div class="field-item even"><img src="http://curealz.org/sites/default/files/styles/large/public/stories/gandy%20paper%20image%208.12%20crop.jpg?itok=RXFwO8Ju" width="442" height="220" alt="" /></div></div></div><div class="field field-name-body field-type-text-with-summary field-label-hidden"><div class="field-items"><div class="field-item even"> <p class="p1">A promising first-in-class drug stimulates the creation of new nerve cells in the brains of Alzheimer's mice and will soon be tested in the brains of human patients, thanks to new research by <a href="http://curealz.org/people/sam-gandy">Dr. Sam Gandy</a>, member of Cure Alzheimer's Fund's Research Consortium, at Mount Sinai School of Medicine in New York.</p>
<p class="p1">A <a href="http://www.nature.com/mp/journal/v19/n11/full/mp201487a.html" target="_blank">new article</a> by Gandy's team just published in the journal <em>Molecular Psychiatry</em> outlines the extraordinary promise of the drug, known as a "mGluR2/3 blocker". Created by the Japanese pharmaceutical firm Taisho and originally studied for depression, the drug acts by stimulating stem cells in the hippocampus to divide and form new nerve cells. What's more, the learning behavior of the Alzheimer's mice being treated with the mGluR2/3 blocker has been sustained at its normal level, in contrast to the steady decline of the mice not being treated.</p>
<p class="p1">mGluR2/3 originally caught the attention of Gandy and his team for its possible ability to inhibit production of the toxic protein Abeta42, which is associated with Alzheimer's disease. With funding from Cure Alzheimer's Fund, they conducted a pilot study of the drug's effects on a particular strain of mice. That study turned out such promising results that it has drawn $1 million in funding from the Veterans Administration "MERIT Review" program that supports Gandy's lab at the James J Peters VA Medical Center in the Bronx. Generous additional funding was also provided by the Louis B Mayer Foundation, the Sarah and Gideon Gartner Foundation, and the <a href="http://www.brightfocus.org/alzheimers/newsupdates/new-experimental-drug-class.html" target="_blank">BrightFocus Foundation</a>.</p>
<p class="p1">The mGluR2/3 blocker has also been administered to healthy young human subjects, and so far has been shown to be safe. The next step for Gandy's team will be to treat elderly human subjects with the drug to test safety in this population before gearing up to test the drug in Alzheimer's disease. With the focus of mainstream Alzheimer's research turning toward prevention, the mGluR2/3 blocker is one of the few drugs that holds promise for repairing brains already damaged by neurodegenerative disease.</p>
<p class="p1">All of these efforts proceed from the international <a href="http://curealz.org/projects/stem-cell-consortium">Stem Cell Consortium</a> formed by Gandy in 2012 and funded by Cure Alzheimer's Fund. "It's extraordinary that in such a short time, we have moved from ordinary skin cells to induced pluripotent stem cells in a petri dish, to lab-generated human nerve cells, and now to a drug that could potentially create those cells inside a human brain," said Gandy. "We realize that we are unlikely to have much impact in late-stage Alzheimer's, but we are cautiously hopeful that this drug might arrest Alzheimer's disease at an early stage so that patients can remain functional for more extended periods." Gandy's mGluR2/3 blocker is one of five brain cell regenerating agents currently undergoing testing in labs around the world. </p>
<p class="p1">"We are so proud of this development," said Cure Alzheimer's chairman <a href="http://curealz.org/people/jeffrey-morby">Jeffrey Morby</a>. "Helping incubate cutting edge science that can gain momentum with federal funding -- this is precisely why Cure Alzheimer's Fund exists."</p>
<p class="p1"> </p>
<p class="p1"><em>David Shenk is a senior advisor to Cure Alzheimer's Fund and author of </em>The Forgetting: Alzheimer's: Portrait of an Epidemic.</p>
</div></div></div><div class="field field-name-field-topics field-type-taxonomy-term-reference field-label-above"><div class="field-label">Keywords:&nbsp;</div><div class="field-items"><div class="field-item even"><a href="/topics/research-updates">Research Updates</a></div><div class="field-item odd"><a href="/topics/drug-discovery">Drug Discovery</a></div></div></div>Tue, 12 Aug 2014 13:52:40 +0000madelson3986 at http://curealz.orgInside the Alzheimer's Lab: Interviews With Our Researchershttp://curealz.org/2014/03/inside-alzheimers-lab-interviews-our-researchers
<div class="field field-name-body field-type-text-with-summary field-label-hidden"><div class="field-items"><div class="field-item even"> <p>Over the past few years, our understanding of Alzheimer’s disease has increased immensely. We can now identify three distinct parts of the disease pathology: early-stage Abeta (amyloid) accumulation, mid-stage development of tau tangles, and late-stage inflammation.</p>
<p>Scientists on our Research Consortium are investigating all three of these points of intervention. On March 6, we talked to Drs. Steven Wagner, David Holtzman, and Rudy Tanzi about how their labs are working to stop Alzheimer’s in its early, middle, and late stages.</p>
<p> </p>
<p><iframe src="http://player.vimeo.com/video/89533690" frameborder="0" width="500" height="281"></iframe></p>
<p><strong>Early-Stage Intervention: Abeta<br /></strong><strong>Steven Wagner, Ph.D.<br /></strong>University of California, San Diego</p>
<p>The Abeta protein has long been recognized as central to the development of Alzheimer’s pathology. Only recently, however, have we come realize that this substance not only causes problems in Alzheimer’s patients, but also plays an important role in the innate immune system. Dr. Steven Wagner is working to produce a drug that will modulate an enzyme called gamma secretase, which is a critical contributor to Abeta production. By regulating rather than eliminating Abeta, Wagner and his lab hope to safely halt the development of Alzheimer’s in its early stages.</p>
<p> </p>
<p><iframe src="http://player.vimeo.com/video/89533689" frameborder="0" width="500" height="281"></iframe></p>
<p><strong>Middle-Stage Intervention: Tau<br /></strong><strong>David Holtzman, M.D.<br /></strong>Washington University in St. Louis </p>
<p>In addition to Abeta, tau tangles, another abnormal aggregation of proteins, are known to cause damage in the Alzheimer’s brain. Dr. Holtzman has recently demonstrated breathtakingly positive results in a proof-of-concept study using antibodies, aimed at stopping the aggregation and spread of tau.</p>
<p> </p>
<p><iframe src="http://player.vimeo.com/video/89544887" frameborder="0" width="500" height="281"></iframe></p>
<p><strong>Late-Stage Intervention: Inflammation<br /></strong><strong>Rudy Tanzi, Ph.D.<br /></strong>Harvard Medical School/Massachusetts General Hospital</p>
<p>The plaques and tangles of the early and middle stages of Alzheimer’s trigger an immune response, which under normal circumstances would help to clear away damaged and unwanted cells. When the cells responsible (microglia) do not function properly, damaging inflammation occurs – “friendly fire” that greatly exacerbates the disease pathology in a vicious cycle. Dr. Tanzi is researching a gene called CD33 that, when deactivated, helps microglial cells to stop this cycle.</p>
</div></div></div><div class="field field-name-field-topics field-type-taxonomy-term-reference field-label-above"><div class="field-label">Keywords:&nbsp;</div><div class="field-items"><div class="field-item even"><a href="/topics/alzheimers-therapy">Alzheimer&#039;s therapy</a></div><div class="field-item odd"><a href="/topics/drug-discovery">Drug Discovery</a></div></div></div>Fri, 21 Mar 2014 19:12:29 +0000madelson3598 at http://curealz.orgFrancis Collins Addresses Senate on Alzheimer's and Dementiahttp://curealz.org/2014/02/francis-collins-addresses-senate-alzheimers-and-dementia
<div class="field field-name-field-video-ref field-type-node-reference field-label-hidden"><div class="field-items"><div class="field-item even"><div id="node-3562" class="node node-video clearfix">
<div class="field field-name-field-video field-type-file">
<object id='cspan-video-player' classid='clsid:d27cdb6eae6d-11cf-96b8-444553540000' codebase='http://fpdownload.macromedia.com/pub/shockwave/cabs/flash/swflash.cab#version=9,0,0,0' align='middle' height='500' width='410'><param name='allowScriptAccess' value='true'/><param name='movie' value='http://static.c-span.org/assets/swf/CSPANPlayer.1393275105.swf?clipid=4485406'/><param name='quality' value='high'/><param name='bgcolor' value='#ffffff'/><param name='allowFullScreen' value='true'/><param name='flashvars' value='system=http://www.c-span.org/common/services/flashXml.php?clipid=4485406&style=full&version=2014-01-23'/><embed name='cspan-video-player' src='http://static.c-span.org/assets/swf/CSPANPlayer.1393275105.swf?clipid=4485406' allowScriptAccess='always' bgcolor='#ffffff' quality='high' allowFullScreen='true' type='application/x-shockwave-flash' pluginspage='http://www.macromedia.com/go/getflashplayer' flashvars='system=http://www.c-span.org/common/services/flashXml.php?clipid=4485406&style=full&version=2014-01-23' align='middle' height='500' width='410'></embed></object> </div>
<div class="content">
<div class="field field-name-field-video-embed-code field-type-text-long field-label-hidden"><div class="field-items"><div class="field-item even"></div></div></div> </div>
</div>
</div></div></div><div class="field field-name-body field-type-text-with-summary field-label-hidden"><div class="field-items"><div class="field-item even"> <p>On Wednesday, February 26, 2014, a U.S. Senate subcommittee heard from several panelists on the state of research, funding and awareness for Alzheimer's disease and related dementias. The first panel was led by Dr. Francis Collins, director of the National Institutes of Health (NIH). In his talk, Dr. Collins describes much of the research being conducted by Cure Alzheimer’s Fund, which is focused on identifying both the causes of Alzheimer’s disease and identifying therapeutic targets for drug discovery to prevent cognitive decline. The session served to bring the Alzheimer's crisis to the attention of politicians, as well as to enhance the public's understanding of current research.</p>
<p>Other presenters at the hearing included Dr. Richard Hodes, director of the National Institute on Aging, and Seth Rogen, actor and founder of Hilarity for Charity, a non-profit raising money for Alzheimer's through comedy events.</p>
</div></div></div><div class="field field-name-field-topics field-type-taxonomy-term-reference field-label-above"><div class="field-label">Keywords:&nbsp;</div><div class="field-items"><div class="field-item even"><a href="/topics/awareness">Awareness</a></div><div class="field-item odd"><a href="/topics/stem-cells">Stem Cells</a></div><div class="field-item even"><a href="/topics/drug-discovery">Drug Discovery</a></div></div></div>Thu, 27 Feb 2014 17:23:39 +0000madelson3563 at http://curealz.orgDrug Development Strategy: Three Points of Attackhttp://curealz.org/2014/01/drug-development-strategy-three-points-attack
<div class="field field-name-body field-type-text-with-summary field-label-hidden"><div class="field-items"><div class="field-item even"> <p>In view of an emerging consensus on how Alzheimer’s disease develops and progresses, the Cure Alzheimer’s Fund Research Consortium aggressively is focusing on three opportunities for possible intervention—at the early stage of the disease, the middle stage and the late stage. This comprehensive strategy addresses the whole picture of how Alzheimer’s disease develops and progresses, and attacks all three points simultaneously.</p>
<p> </p>
<p class="Subhead1"><strong>What we know</strong></p>
<p>For too long, Alzheimer’s research has been distracted by arguments over “plaques” vs. “tangles.” Some thought the key to treatment was clearing plaques, while others argued that eliminating tangles would cure the disease. Most researchers now agree it is necessary to attack both plaques and tangles, as well as other elements of the pathology, to stop the disease’s progression.</p>
<p>The Research Consortium now shares the understanding that Alzheimer’s is a vicious cycle of destruction that begins with the production of excessive beta-amyloid peptides (Abeta) that aggregate into clusters called “oligomers,” then proceeds to the creation of tangles from the protein tau that originate inside cells but that recently have been shown to spread to other cells. Both of these create inflammation in the brain, which stimulates more creation of Abeta, thus continuing a cycle that is deadly for brain cells. This destructive cycle can be envisioned as follows:</p>
<p> </p>
<h4 class="Subhead1"><strong><img style="float: right; margin-left: 10px; margin-right: 10px;" src="/sites/default/files/stories/2013_Q4Report_simpleDiagram_0.jpg" alt="" width="375" height="827" />Intervention point - A</strong></h4>
<h4 class="Subhead1"><strong style="font-family: Verdana, sans-serif; font-size: 12px;">Early stage</strong></h4>
<p>Ideally, this cycle would be stopped at what is thought to be its origin: the overproduction of the protein Abeta. This approach has been pursued broadly for a number of years, so far to little avail. Some drug candidates have proven too toxic; others were ineffective at safe doses. Recent research led by <a href="http://curealz.org/people/robert-moir">Robert Moir, Ph.D.</a>, of Massachusetts General Hospital (MGH) and funded by Cure Alzheimer’s Fund has shown the Abeta protein is an important and integral part of the innate immune system, and therefore maintaining an appropriate balance of the protein rather than eliminating it may be the right therapeutic approach.</p>
<p>Consortium researchers are pursuing a number of ways to control Abeta production and clearance. Perhaps the most promising research is taking place in the University of California, San Diego lab of <a href="http://curealz.org/people/steven-wagner">Steven Wagner, Ph.D.</a>, and the MGH lab of <a href="http://curealz.org/people/rudy-tanzi">Rudy Tanzi, Ph.D.</a> Their approach has been to develop drugs to modulate an enzyme called gamma secretase, which is a critical contributor to Abeta production. Their effort has been so successful that the compounds they have developed have been adopted by the National Institutes of Health (NIH) as part of its fast-track, high-priority “Blueprint” program.</p>
<p>“We’re making excellent progress,” reports Wagner. “We have developed a number of compounds and are currently testing them with the hopes of narrowing the list down to one or two clinical candidates.” Tanzi echoes this optimism, saying, “We are hopeful that this project will lead to our gamma secretase modulators in clinical trials over the next year or so.”</p>
<p> </p>
<h3 class="Subhead1"><strong>Intervention point - B<br /></strong><strong style="font-family: Verdana, sans-serif; font-size: 12px;">Middle stage</strong></h3>
<p>In concert with efforts to contain Abeta in the earliest possible stage, consortium members also are pursuing strategies that would zero in on the formation and spread of tau tangles. Foremost among these is the effort led by consortium member <a href="http://curealz.org/people/david-holtzman">David Michael Holtzman, M.D.</a>, based at Washington University in St. Louis, who recently demonstrated breathtakingly positive results in a proof-of-concept study aimed at stopping the aggregation and spread of tau in the middle stages of the disease.</p>
<p>Holtzman’s study, in collaboration with Washington University’s Marc Diamond, M.D., assembled a variety of potential tau antibodies and introduced them into the brains of genetically engineered mice. Based on a hypothesis that the toxic form of tau gets “spit out” of nerve cells and subsequently “infects” other nearby healthy neurons, the study demonstrated that the antibodies were able to conclusively stop this spreading process; this subsequently led to cognitive improvements in the mice. Their study was published in the journal Neuron in September 2013. The results were “fantastic,” commented the German Center on Degenerative Diseases’ Eckhard Mandelkow, Ph.D., to the Alzheimer’s Research Forum last September. “It explains why antibody therapy might work for tau pathology.”</p>
<p> </p>
<h3 class="Subhead1"><strong>Intervention point - C</strong></h3>
<p class="Subhead2"><strong>Late stage</strong></p>
<p>Consortium members also are pursuing efforts to curtail Alzheimer’s-related brain inflammation. One of the most promising efforts involves an attempt to inhibit the activity of a gene called CD33. In 2008, Tanzi’s group first discovered this gene’s relationship to late-onset Alzheimer’s in a large family-based, genome-wide association study (GWAS). In 2013, the group described in the journal Neuron the gene’s regulation of immune-response microglial (helper) cells in the aging brain. Microglia normally clear away damaged and unwanted cells in the brain; if they are not functioning properly, damaging inflammation can occur. When Tanzi’s group deactivated CD33 in AD mouse models, more Abeta was cleared away by the microglial cells, leading to diminished amyloid plaque burden and less inflammation. </p>
<p>The Tanzi lab is attempting to develop effective CD33 inhibitors by screening compounds and antibodies that inhibit CD33 function. The compounds showing the most promise will be tested in AD mouse models. “There’s still some work to do here,” says Tanzi, “but interrupting CD33 could turn out to be a powerful therapeutic strategy.”</p>
<p> </p>
<p class="Subhead1"><strong>Following the science</strong></p>
<p>“We follow the science, wherever it leads,” says Cure Alzheimer’s Fund Chairman Jeffrey Morby. “Alzheimer’s is a complex disease and we’re proud to support our Research Consortium in this multipronged effort to defeat it at each stage.”</p>
<p> </p>
<p><em>Want to learn more? David Holtzman, Rudy Tanzi and Steve Wagner will further discuss their research findings in an Alzstream video, moderated by David Shenk, available starting on March 20. The video will be posted at <a href="http://www.curealz.org">www.curealz.org</a> and sent out via e-blast to everyone on our mailing list. If you would like to be added, please let us know at<strong> <a href="mailto:info@curealz.org">info@curealz.org</a></strong>.</em></p>
</div></div></div><div class="field field-name-field-topics field-type-taxonomy-term-reference field-label-above"><div class="field-label">Keywords:&nbsp;</div><div class="field-items"><div class="field-item even"><a href="/topics/drug-discovery">Drug Discovery</a></div><div class="field-item odd"><a href="/topics/alzheimers-treatment">Alzheimer&#039;s Treatment</a></div></div></div>Tue, 28 Jan 2014 16:02:32 +0000madelson3528 at http://curealz.orgDesperate For a Cure: The Search for New Alzheimer's Treatmentshttp://curealz.org/2013/10/desperate-cure-search-new-alzheimers-treatments
<div class="field field-name-body field-type-text-with-summary field-label-hidden"><div class="field-items"><div class="field-item even"> <p>"Desperate For A Cure: The Search For New Alzheimer's Treatments", a new five-part series by NPR's Sean Corcoran, aired this week on WCAI and will air again next week on WGBH in Boston.</p>
<p>In each segment, Corcoran discusses current research towards understanding and curing Alzheimer's disease. Among those interviewed are several members of Cure Alzheimer's Fund's Research Consortium, including Robert Moir, Ph.D., Rudy Tanzi, Ph.D, and Steve Wagner, Ph.D. Topics covered range from methods of clearing toxic amyloid beta from the brain to brain scans and challenges regarding upcoming drug trials.</p>
<p>One constant theme throughout the program is the struggle to find funding for Alzheimer's disease research. "We are not knowledge-constrained; we're budget constrained," says Dr. Rudy Tanzi. He explains that while current drugs in development are promising, pharmaceutical companies are "frustrated now with the failures of the past". The fact that older drugs were not successful in treating AD is making it difficult for new, better drugs to get funded.</p>
<p>But Corcoran stresses that we don't have time to be so hesitant about new potential therapies. With forecasts of 16 million AD sufferers by 2050, effective treatments are needed more than ever.</p>
<p>Luckily, some researchers are having success with receiving funding from the National Institutes of Health. Dr. Steve Wagner, whose drug development program was boosted by Cure Alzheimer's Fund back in 2009, is now receiving a 5-year, $1 million-dollar grant from NIH.</p>
<p>If you'd like to learn more about the exciting research Wagner and others are doing, you can now listen to or read all five segments of "Desperate For A Cure" on <a href="http://capeandislands.org/post/taking-shots-goal-search-new-alzheimers-treatments?nopop=1">WCAI's website</a>.</p>
</div></div></div><div class="field field-name-field-topics field-type-taxonomy-term-reference field-label-above"><div class="field-label">Keywords:&nbsp;</div><div class="field-items"><div class="field-item even"><a href="/topics/drug-discovery">Drug Discovery</a></div><div class="field-item odd"><a href="/topics/alzheimers-treatment">Alzheimer&#039;s Treatment</a></div><div class="field-item even"><a href="/topics/alzheimers-therapy">Alzheimer&#039;s therapy</a></div></div></div>Fri, 04 Oct 2013 16:46:24 +0000madelson3297 at http://curealz.orgTargretin Fails: High Hopes Dashed for a New Treatment for Alzheimer’shttp://curealz.org/2013/05/targretin-fails-high-hopes-dashed-new-treatment-alzheimer%E2%80%99s
<div class="field field-name-body field-type-text-with-summary field-label-hidden"><div class="field-items"><div class="field-item even"> <p>While many were anxious to accept initial findings showing a drug known as Targretin’s “too good to be true” lab results with Alzheimer’s disease, subsequent attempts to confirm and replicate the original data regarding the ability of Targretin to remove amyloid plaques, the cardinal lesion of the disease, have largely failed. Cure Alzheimer’s Fund Research Consortium members <a href="http://www.curealz.org/people/sangram-sisodia">Dr. Sangram Sisodia</a>, professor of neuroscience at the University of Chicago and <a href="http://www.curealz.org/people/robert-vassar">Dr. Robert Vassar</a>, professor of cell and microbiology at Northwestern University along with several other groups have completed revealing new research which contradicts earlier claims for relief of Alzheimer’s symptoms and the hopeful promise of a new effective Alzheimer’s therapy.</p>
<p>Targretin’s story began in early 2011 when <a href="http://www.curealz.org/people/gary-landreth">Dr. Gary Landreth</a> of Case Western Reserve shared startling lab results with Alzheimer’s research colleagues. His lab shared data that showed extensive and almost immediate clearing of the amyloid beta (Abeta) plaques that are the telltale signature of Alzheimer’s disease, the largest disease among several types of dementia. Cure Alzheimer’s Fund supported a proposal from the Landreth lab in the summer of 2011 to confirm some of the results of the study. In January of 2012, Landreth and colleagues published a paper, essentially with the original findings, in the prestigious journal SCIENCE to great acclaim by the Alzheimer’s research field. At last, it seemed, here was a breakthrough for the over 5 million patients suffering from Alzheimer’s symptoms present in an existing drug, already approved by the FDA that appeared to attack the disease directly and not just the symptoms.</p>
<p>But some researchers remained skeptical. Scientists from Cure Alzheimer’s Fund’s Research Consortium requested more data from the Landreth lab which was forthcoming. Landreth and colleagues suggested that on the basis of the impressive results, a limited human trial be done to begin to assess the efficacy of the drug against Alzheimer’s in human, not just lab mice. Cure Alzheimer’s Fund was interested in participating in that Phase 1 trial, but still had concerns about the original data.</p>
<p>“We were surprised and excited, even stunned when we first saw these results presented at a small conference,” said Sisodia, in a <a href="http://www.medicaldaily.com/articles/15850/20130523/targretin-alzheimers-drug-alzheimers-plaque-drug-retrial.htm">Medical Daily story</a> highlighting his co-authored response to Landreth’s initial findings. “The mechanism of action made some sense, but the assertion that they could reduce the areas of plaque by 50 percent within three days and by 75 percent in two weeks, seemed too good to be true.”</p>
<p>The promise of a potential breakthrough for Alzheimer’s patients was strong enough for Cure Alzheimer’s Fund that it supported an additional study by Sisodia and Robert Vassar of Northwestern University in the spring of 2012 after release of the Landreth paper to try again to confirm the Landreth lab results.</p>
<p>Meanwhile, the media had begun to tell this story and Alzheimer’s patients were eager to try this drug themselves. They implored their doctors to find Targretin for them and prescribe it “off label”. Some did and still are. Some researchers such as Dr. Sam Gandy of Cure Alzheimer’s Fund Research Consortium, Robert Vassar and others urged their colleagues and neurologist not to prescribe this drug until more data was gathered about a) the effectiveness of the drug against Alzheimer’s and b) the nature of side effects of the drug in Alzheimer’s patients which were completely untested.</p>
<p>Today, three reports including Sisodia and Vassar’s co-authored work will be published in Science where Sisodia writes, "There is absolutely no reduction in amyloid levels in the brains of mice treated with this compound."</p>
<p>Gary Landreth has told Nature, another prestigious science publication: “It was our expectation other people would be able to repeat this… Turns out that wasn’t the case, and we fundamentally don’t understand that.”</p>
<p>What do we learn from this?</p>
<ol><li>Do not shy away from risk. Landreth and his colleagues are to be applauded for their original insight and attempt to find the much-dreamed of short cut to a cure for Alzheimer’s. Here they had an existing, FDA-approved drug that seemed to work. Wouldn’t that be wonderful? Try it; work it through the lab process to determine how it affects the pathology and then figure out if it is safe to use in this context. Even if it seems like a long-shot, if it can prevent misery and save lives, it’s worth it.</li>
<li>If it is “too good to be true”, it probably isn’t. Appropriate skepticism is part of the “scientific method” and rigorous follow up for confirmation is absolutely essential. Sharing of data both pre and post publication is critical for this function. Again, the Landreth lab is to be commended for sharing that data with others. But we also look to the originators of the data to be skeptical, too, and to keep confirming their findings in their own labs and in working with others.</li>
<li>Do not use a drug or compound in humans until the lab and animal data make sense. It is so tempting to move to humans to try to abrogate suffering as fast as possible. And again, this is and FDA approved drug --- how bad could it be? But we find, in fact, that not only is its efficacy in question, but the side effects appear to be particularly bad in Alzheimer’s patients. The differences between the original purpose and the “off label” purpose come in dosage to be effective and duration of exposure, all untested in Alzheimer’s patients and before the lab results could be confirmed.</li>
<li>Go to the root of the problem. The “existing drug” fix would, indeed, solve a lot of problems in finding a “cure” for Alzheimer’s disease. It would obviate years of clinical trials, save millions if not billions of dollars, and provide almost instant effective intervention and perhaps prevention of the disease. HOWEVER, without knowing fundamentally how the drug affects the basic mechanisms of the pathology, its efficacy and safety are in question.</li>
</ol><p>Cure Alzheimer’s Fund believes that we cannot find the cure without understanding the cause. The dementia that is Alzheimer’s is rooted in genetics. The <a href="http://www.curealz.org/projects/alzheimer%E2%80%99s-genome-project%E2%84%A2">Alzheimer’s Genome Project</a> and its newest phase, the <a href="http://www.curealz.org/projects/whole-genome-sequencing">Whole Genome Sequencing Project</a> of Alzheimer’s, co-funded by Cure Alzheimer’s Fund and the National Institutes of Mental Health and led by <a href="http://www.curealz.org/people/rudy-tanzi">Dr. Rudy Tanzi</a> of Massachusetts General Hospital and Harvard Medical School and Chairman of Cure Alzheimer’s Fund’s Research Consortium is designed to a) identify all the genes that confer risk or provide prevention for the disease, and b) determine the function of those genes as they relate to Alzheimer’s pathology. Similar studies are underway by others, but the Cure Alzheimer’s Fund project will be the largest private, family-based study of the Alzheimer’s genome in the world.</p>
<p>That is important because without understanding these basics, we risk spending years and billions of dollars “shooting in the dark” to intervene in the disease without knowing quite how it starts and progresses. There have been spectacular failures of promising Alzheimer’s drugs because those drugs were not grounded in the fundamentals of the causes of the disease.</p>
<p>We are getting closer. Alzheimer’s researchers are closer than ever to consensus about the origins of the disease and its biological progression, aided in large part by these genetic studies and the biochemistry of the proteins those genes produce. But we are not quite there yet. There are also promising therapies under development, the more recent ones based on much better understandings of the disease. One example is a “gamma secretase modulator” developed by <a href="http://www.curealz.org/people/steve-wagner">Steve Wagner</a> of the University of California at San Diego and Rudy Tanzi of Massachusetts General Hospital and Harvard Medical School which will modulate the production of Abeta at its origin to help keep it in proper balance. The approach has been so attractive that the National Institutes of Health has adopted the compound as part of its prestigious “Blueprint” program for fast-tracking promising compounds into drug development.</p>
<p>There are other examples of good, solid therapies now being developed from a much better understanding of the origins of the disease. But again, we do not yet have the kind of working understanding of the origins and progression of the disease that will significantly shorten the time from drug discovery to drug availability.</p>
<p>Until then, we need to keep working hard at understanding those origins and how the pathology plays out and when it plays out. It is becoming increasingly clear that this disease begins much earlier --- perhaps decades --- than symptoms are exhibited. Therefore we need to find ways not only to interrupt the pathology in those people already affected, but prevent it from starting or progressing in those people at greatest risk. A tall but necessary order.</p>
<p>Finally and again, Cure Alzheimer’s Fund applauds the Landreth lab for its aggressive pursuit of a promising therapy and equally applauds the skepticism and hard work of those who, while wishing it was true, needed to find out for sure.</p>
<p>Tim Armour</p>
<p>President and CEO</p>
<hr /><h3>Related</h3>
<p><a href="/node/319">Why don’t the drugs work?</a></p>
</div></div></div><div class="field field-name-field-topics field-type-taxonomy-term-reference field-label-above"><div class="field-label">Keywords:&nbsp;</div><div class="field-items"><div class="field-item even"><a href="/topics/research-updates">Research Updates</a></div><div class="field-item odd"><a href="/topics/drug-discovery">Drug Discovery</a></div><div class="field-item even"><a href="/topics/alzheimers-treatment">Alzheimer&#039;s Treatment</a></div></div></div>Fri, 24 May 2013 21:28:57 +0000llyle3062 at http://curealz.org